Acute on Chronic Interstitial Nephritis Linked to a Novel IRF2BP2 Variant of Uncertain Significance

Introduction: The association of Interstitial nephritis (IN) with primary immunodeficiency (PID) including Common Variable Immunodeficiency (CVID) is less recognized. We present a unique case of IN in a patient with CVID, highlighting the overlap between immunodeficiency and nephrological complications to discuss its suspected link to a novel IRF2BP2 variant of uncertain significance (VUS). Case Description: A 28-year-old male diagnosed with CVID suspected to be due to his IRF2BP2 VUS mutation. He has had enteropathy, interstitial lung disease, recurrent infections (sinusitis, pneumonias, skin abscesses, immune thrombocytopenia, interstitial lung disease, interstitial nephritis, splenomegaly, lymphadenopathy, dependent on immunoglobulin replacement therapy (IgRT), corticosteroids, immunosuppressants (rituximab, Cellcept) and underwent splenectomy. He presented with serum creatinine rise to 2.9 mg/dL over one year. Serologic workup was unremarkable. Renal biopsy revealed chronic active tubulointerstitial nephritis related to CVID, proximal tubule isometric cytoplasmic vacuolization likely due to IgRT, and focal proliferative immune complex-mediated glomerulonephritis due to infection. Immunohistochemistry revealed T cells mixed with scattered eosinophils and macrophages. Prednisone was initiated with improvement in serum creatinine (Cr) to 2mg/dL, but therapy was truncated due to infection and steroid related intolerable side effects. Calcineurin inhibitors were deferred due to renal dysfunction. mTOR inhibitors were avoided due to his history of severe mucositis on sirolimus. Finally, mycophenolate was discussed as a second option while he awaited further treatment options for CVID. Discussion: This case underscores the complex interplay between PID and renal pathology, where CVID-associated immune dysregulation can manifest as chronic interstitial nephritis, including role of IRF2BP2 VUS in immune-mediated kidney injury.Hematoxylin and Eosin stain: dense lymphohistiocytic interstitial inflammation with occasional eosinophils